Cryan J F, McGrath C, Leonard B E, Norman T R
Department of Psychiatry, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia.
Eur J Pharmacol. 1998 Jul 3;352(1):23-8. doi: 10.1016/s0014-2999(98)00402-6.
The realisation that pindolol may accelerate the effects of some antidepressant drugs in clinical trials has added extra impetus to the search for faster acting antidepressants. Currently, no animal model of depression can identify potential faster acting antidepressant drugs or drug combinations. In this study, we investigate the effects of combining pindolol (2 mg/kg, s.c., bid) with the antidepressant paroxetine (2.5 mg/kg, i.p., bid) in the olfactory bulbectomised rat, an animal model of chronic (but not acute) antidepressant activity. Ambulation scores were measured in separate groups of rats, following 3, 7 and 14 days of treatment. Further, we simultaneously study adaptive changes in 5-HT1A receptor function, utilising alterations in the hypothermic response to the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Pindolol in combination with paroxetine attenuated the hypothermic effects of 8-OH-DPAT as early as 3 days with a full reversal evident following 7 days, whereas paroxetine alone did so after 14 days only. Likewise, paroxetine alone reversed the olfactory bulbectomy-induced hyperactivity in the open field following 14 days of treatment only, this being the normal time of an 'antidepressant' response in this model. However, the group treated with both paroxetine and pindolol failed to reverse the hyperactive response. This suggests that a factor intrinsic to pindolol antagonises the behavioural effects of paroxetine in the olfactory bulbectomised rat. It also demonstrates that the reversal of this aspect of the olfactory bulbectomy-induced behavioural syndrome is insensitive to the potential faster onset of antidepressant action induced by pindolol. The ability of the combination group to attenuate the hypothermic effects of 8-OH-DPAT much faster further emphasises the role of the 5-HT1A receptor in the mechanism of action of antidepressants and as a target for the development of faster acting antidepressants. However, an animal model sensitive to the effects of any such compound and the actions of pindolol remains elusive.
在临床试验中发现吲哚洛尔可能会加速某些抗抑郁药物的作用，这为寻找起效更快的抗抑郁药物增添了额外动力。目前，尚无抑郁症动物模型能够识别潜在的起效更快的抗抑郁药物或药物组合。在本研究中，我们在嗅球切除大鼠（一种慢性（而非急性）抗抑郁活性的动物模型）中研究了吲哚洛尔（2毫克/千克，皮下注射，每日两次）与抗抑郁药帕罗西汀（2.5毫克/千克，腹腔注射，每日两次）联合使用的效果。在治疗3、7和14天后，对不同组的大鼠测量其活动评分。此外，我们利用对5-HT1A受体激动剂8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT）的体温降低反应的变化，同时研究5-HT1A受体功能的适应性变化。吲哚洛尔与帕罗西汀联合使用早在3天时就减弱了8-OH-DPAT的体温降低作用，7天后完全逆转，而单独使用帕罗西汀仅在14天后才出现这种情况。同样，单独使用帕罗西汀仅在治疗14天后才逆转嗅球切除诱导的旷场活动亢进，这是该模型中“抗抑郁”反应的正常时间。然而，同时接受帕罗西汀和吲哚洛尔治疗的组未能逆转活动亢进反应。这表明吲哚洛尔的内在因素拮抗了帕罗西汀在嗅球切除大鼠中的行为效应。这也表明，嗅球切除诱导的行为综合征这一方面的逆转对吲哚洛尔诱导的抗抑郁作用潜在更快起效不敏感。联合治疗组更快减弱8-OH-DPAT体温降低作用的能力进一步强调了5-HT1A受体在抗抑郁药作用机制中的作用以及作为起效更快的抗抑郁药开发靶点的作用。然而，对任何此类化合物的作用和吲哚洛尔敏感的动物模型仍然难以捉摸。
